The cadiac responses to stress and cardiomyopathy share a common feature: altered signaling through G protein-coupled receptor (GPCR) pathways that regulate the homeostatic balance of signaling in the heart. Restoration of normal homeostasis in cardiomyopathy is the basis for medical therapies that target GPCRs, such as the beta-adrenergic receptor. In the heart, signals derived from over 20 different GPCRs are communicated through five major G protein pathways. In this proposal, I will use cardiac-targeted, constitutive activation of the Gi and Gq pathways to define the in vivo responses of the G protein pathways that inhibit adrenylyl cyclase and stimulate phospholipase C, respectively. To gain tissue-specific, temporally regulated control of G protein signals, two powerful biological approaches are combined. First, the primary signaling component of each G protein (Galpha) can be constitutively activated (Galpha*) so that each of the pathways (Galphai* and Galphaq*) can be examined. Second, the tetracycline transactivator (tet) system allows inducible expression of these constitutively active forms of Galpha in the adult mouse heart, avoiding possible developmental effects. Analysis of the transgenic mice will include detailed physiologic measurements. These studies will provide answers to questions, such as: Which G protein pathway will cause cardiomyopathy? How does each G protein pathway alter the homeostatic balance of the heart? A comprehensive, focused study of G protein signaling in the heart is proposed with two specific aims: (1) to selectively activate the Galphai and Galphaq pathways in the heart by conditionally expressing mutationally activated subunits (Galphai* and Galphaq*) in transgenic mouse hearts; and (2) to determine the physiological effects of G protein pathways in a normal adult mouse heart.